The physiological pharmacokinetics of HDMTX has been more fully characterized principally in canines. Plasma clearance curves were found to be biphasic up to 48 hours in animals with cannulated bile ducts. The plasma half-lives were about 2 hours and 7.4 hours. Renal clearance was consistent with the glomerular filtration rate of 4.25 cc/min/kg. A multicompartment physiological pharmacokinetic model was formulated and applied to the canine data. It was found that the second half-life could be accounted for by efflux of drug from the deep compartments of spleen, gut and marrow provided the Michaelis' K efflux/K influx was 3 and maximum efflux transport velocities were halved from the initial estimates made in rat systems. These changes still allowed close fits to the rat tissue and plasma data however. Charcoal hemoperfusion was investigated pharmacokinetically at doses of 10 mg/kg and found to be incapable of emptying the deep compartments in times less than 50 hours, thus limiting its ability to provide an alternative form of rapid rescue. Langmuir adsorption constants appropriate for MTX were determined for charcoal and it was found that rapid saturation of the filter is not limiting. Finally, with the ultimate aim of better characterizing the toxicity effects of MTX on normal bone marrow, the formulation and programming of a partial differential cell kinetic model was completed (in a joint effort with CA12369), and initial attempts were made to introduce control parameters capable of representing the normal marrow populations. Proliferation and differentiation are described simultaneously by a four-variable plus time cell density function.